Age Related Macular Degeneration (AMD) is the leading cause of untreatable blindness in individuals over the age of 65. Currently, there is no effective treatment available for most patients with AMD. It is widely accepted that AMD is a multi-factorial disease involving the interaction of genetic and environmental factors. Genetic studies have identified a number of chromosomal loci that harbor potential AMD susceptibility genes. We and others have recently identified genetic variants in several genes [such as complement factor H (CFH), toll-like receptor 4 (TLR4) and apolipoprotein E (APOE)] that have been associated with susceptibility to AMD. The primary goals of our research are to dissect genetic and molecular mechanism(s) underlying AMD pathogenesis. In this project, we propose to test the following hypotheses: (i) genetic variations in multiple susceptibility loci predispose individuals to AMD pathogenesis; and (ii) some of the susceptibility loci encode gene products that are involved in stress response, lipid and/or cholesterol metabolism, and immune-modulation. The specific aims are:(1) to collect detailed clinical findings, family history, ancillary data (such as, smoking and diet), and blood/DNA samples from1500 unrelated AMD probands and their family members and 1000unrelated age-(andethnically) matched controls; (2) to refine the critical genomic regions on chromosomes 5p, 9q, 10q and 22q,which are suggested to harbor AMD susceptibility genes, using extensive single nucleotide polymorphism (SNP)-based association studies and to identify the genetic variations that are associated with late-stage AMD in our cohort; (3) to perform association studies in our cohort of case-controls using SNP markers from 100 selected candidate genes that encode proteins involved in stress response, lipid /cholesterol transport, and immune-modulation; and (4) to perform whole genome scan in a second independent sample of 400-500 AMD relative-pairs to identify and validate novel and established AMD susceptibility loci. Identification of susceptibility genes (andgenetic variants) will advance our understanding of molecular and cellular pathways that contribute to the pathogenesis and progression of AMD. In addition, our proposed studies may lead to identification of diagnostic markers for AMD and possibly development of new therapies.